The EAG (ether-à-go-go) family of voltage-gated K+ channels are important regulators of neuronal and cardiac action potential firing (excitability) and have major roles in human diseases such as epilepsy, schizophrenia, cancer, and sudden cardiac death. A defining feature of EAG (Kv10–12) channels is a highly conserved domain on the N terminus, known as the eag domain, consisting of a Per–ARNT–Sim (PAS) domain capped by a short sequence containing an amphipathic helix (Cap domain). The PAS and Cap domains are both vital for the normal function of EAG channels. Using heme-affinity pulldown assays and proteomics of lysates from primary cortical neurons, we identified that an EAG channel, hERG3 (Kv11.3), binds to heme. In whole-cell electrophysiology experiments, we identified that heme inhibits hERG3 channel activity. In addition, we expressed the Cap and PAS domain of hERG3 in Escherichia coli and, using spectroscopy and kinetics, identified the PAS domain as the location for heme binding. The results identify heme as a regulator of hERG3 channel activity. These observations are discussed in the context of the emerging role for heme as a regulator of ion channel activity in cells.

中文翻译：

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在神经元电压门控钾通道中发现血红素结合域。

EAG (ether-à-go-go) 电压门控 K+ 通道家族是神经元和心脏动作电位放电（兴奋性）的重要调节剂，在癫痫、精神分裂症、癌症和心源性猝死等人类疾病中发挥重要作用. EAG (Kv10-12) 通道的一个定义特征是 N 末端的高度保守结构域，称为 eag 结构域，由一个 Per-ARNT-Sim (PAS) 结构域组成，该结构域由一个包含两亲螺旋 (Cap领域）。PAS 和 Cap 域对于 EAG 通道的正常功能都至关重要。使用血红素亲和力下拉分析和初级皮层神经元裂解物的蛋白质组学，我们发现 EAG 通道 hERG3 (Kv11.3) 与血红素结合。在全细胞电生理学实验中，我们发现血红素抑制 hERG3 通道活性。此外，我们在大肠杆菌中表达了 hERG3 的 Cap 和 PAS 结构域，并使用光谱学和动力学将 PAS 结构域确定为血红素结合的位置。结果将血红素确定为 hERG3 通道活性的调节剂。这些观察结果在血红素作为细胞中离子通道活性调节剂的新兴作用的背景下进行了讨论。